The present invention relates to medical devices using Time-Reversal Acoustics (TRA) methods for ultrasound-assisted therapy. One advantageous example of such therapy is needle-based targeted drug delivery into a tumor. Enhanced penetration of drug into the tumor is achieved by subjecting the tumor tissue to ultrasound energy which is focused at the tumor location using the method of the invention. More particularly, a beacon for focusing ultrasound energy is provided at the tip of a dual-function needle, which delivers the drug into the treated tissue and at the same time acts as a hydrophone enabling TRA system to focus ultrasound exactly at the site where the drug was injected.
Focusing of ultrasonic waves is a fundamental aspect of most medical applications of ultrasound. The efficiency of ultrasound focusing in biological tissues is often significantly limited by spatial heterogeneities in sound velocity in tissues and the presence of various reflective surfaces and boundaries. The refraction, reflection and scattering of ultrasound in inhomogeneous media can greatly distort focused ultrasound field. There are many methods for improving the ultrasonic focusing in complex media based on the phase and amplitude corrections in focusing system but they are often too complicated and in some cases do not provide necessary improvement. The concept of TRA developed initially by M. Fink of the University of Paris provides an elegant possibility of both temporal and spatial concentrating of acoustic energy in highly inhomogeneous media. The TRA technique is based on the reciprocity of acoustic propagation, which implies that the time-reversed version of an incident pressure field naturally refocuses on its source. The general concept of TRA is described in an article by Fink, entitled “Time-reversed acoustics,” Scientific American, November 1999, pp. 91-97, which is incorporated herein by reference. U.S. Pat. No. 5,092,336 to Fink, which is also incorporated herein by reference, describes a device for localization and focusing of acoustic waves in tissues.
An important issue in the TRA method of focusing acoustic energy is related to obtaining initial signal from the target area. It is necessary to have a beacon to provide an initial signal from the focal region. In the TRA systems described in the prior art, most common beacon is a hydrophone placed at the chosen target point. Other possible beacons are highly reflective targets that provide an acoustical feedback signal for TRA focusing of acoustic beam.
Remarkably, scattering and numerous reflections from boundaries, which may greatly limit and even completely diminish conventional focusing, lead to the improvement of the focusing ability of the TRA system. Fink et al. have demonstrated a strong robustness of TRA focusing: the more complex the medium, the sharper the focus.
The advantages of the TRA-based focusing systems (TRA FS) over conventional ultrasound focusing are as follows:                1. TRA FS is capable to precisely deliver ultrasound energy to the chosen region regardless of the heterogeneity of the propagation medium, for example behind the ribs or inside the skull. The ability to effectively localize ultrasound energy and avoid exposure of surrounding tissues is important in many medical applications including ultrasound surgery and the ultrasound enhanced drug delivery.        2. TRA FS can produce more effective spatial concentration of ultrasound energy than traditional systems; the focus volume can approach ultrasound diffraction limit, it can be spherical rather than elongated ellipsoidal typically formed by most traditional focusing systems.        3. TRA FS can produce pulses with arbitrary waveforms in a wide frequency band. Ability to generate various waveforms is important in many applications, for example for optimizing the outcome of the ultrasound stimulated drug delivery where the main mechanism of ultrasound action, sonoporation, is related to cavitation and the threshold of cavitation depends strongly on frequency and the form of the applied signal.        
Several examples of TRA FS employing a passive ultrasound reflector or an active ultrasound emitter as a TRA beacon are described in the U.S. Pat. No. 7,201,749 to Govari et al. as well as a European Patent Application No. EP1449564, all of which are incorporated herein by reference. Described is a TRA-based high intensity ultrasound system designed for isolation of pulmonary veins. The beacons, described in these references, are active or passive piesotransducers designed to reflect or emit ultrasound signal to be detected by an array of transducers. In case of an active beacon, the electrical energy is typically delivered thereto via electrical leads from the control unit. The electrical energy is converted by the active beacon into the acoustic energy and transmitted to the outside the body where it is picked up by outside sensors to determine the exact location of the beacon. Alternatively, the beacon may comprise a passive ultrasound reflector, such as the one having a geometry that produces a sharp and easily distinguishable ultrasound signature. Alternative designs of the reflector include the design with substantially higher reflectivity of the ultrasound signal then that of the surrounding tissues, including the design of the beacon with predefined resonant frequency and high Q or a bubble containing an ultrasound agent.
An important area of medical application of ultrasound is targeted drug delivery, specifically for cancer treatment. Tumor chemotherapy is often associated with severe side effects caused by the interactions of cytotoxic drugs with healthy tissues. In addition, tumor cells often develop resistance to drugs in the course of chemotherapy (cross-resistance or multi-drug resistance). Direct injection of drugs in the tumor substantially reduces or eliminates side effects of chemotherapy and increases therapeutic windows of drugs.
Acoustically-activated drug delivery systems are typically therapeutic agents bound to nano- or micro-scale carriers. These are administered to a patient and then activated by extracorporeal ultrasound transducers. Acoustic activation releases the therapeutic agent and induces cavitation that enhances drug uptake in the patient's cells. A high dosage of toxic drugs may be delivered to a point of interest while minimizing negative side effects.
Acoustic activation technology shows promise for the treatment of drug-resistant cancer tumors and other diseases. Triggering the intracellular drug uptake by focused ultrasound enhances treatment efficacy. Ultrasound is proven to be an effective drug delivery modality. An advantage of ultrasound in this application is that it is non-invasive, can penetrate deep in the interior of the body, and can be carefully controlled via a number of parameters including frequency, power density, duty cycle, and time of application. Physicians do not currently have a means to accurately sonicate only an area of interest where the drug has been injected, in order to improve drug uptake to diseased cells and reduce side effects to healthy tissue.